Pancreatic ductal adenocarcinoma is a truly devastating disease. Every year, 40,000 Americans are diagnosed with pancreatic cancer; most of them die within one year and less than 5% of those diagnosed with pancreatic cancer have 5 years survival. Alcoholic chronic pancreatitis and smoking are major established risk factors for pancreatic cancer. However, little is known about how they initiate and promote the disease. We hypothesize that alcoholic pancreatitis induces fibrosis leading to apoptosis inhibition; whereas, tobacco smoke inhibits autophagy and apoptosis. These effects when combined with K-ras genetic mutation, which is present in 90% of pancreatic cancer patients, promote pancreatic carcinogenesis. Our preliminary data indicate that Nox4- NADPH oxidase and Akt kinase mediate the carcinogenic effects of alcoholic pancreatitis and smoking. In this project we propose to develop a mouse model of pancreatic cancer that combines alcoholic pancreatitis, smoking exposure, and K-ras genetic mutation. We propose to test the effect of alcoholic pancreatitis and tobacco smoke on the tumorigenesis and survival pathways in pancreas from mice with pancreas-specific K-ras mutation, and in wild type mice. We will complement in vivo results with the in vitro measurements of the effects of smoking on survival pathways and underlying signaling mechanisms in PanIN cells and in pancreatic ductal cells. Finally, we will develop a preventive strategy by using the data of the mechanistic studies. We will apply Nox4 and Akt inhibitors to prevent pancreatic carcinogenesis. The Specific Aims of this proposal are: 1. Determine the effect of alcohol on the pancreatitis-induced fibrosis, survival, and carcinogenesis in wild type and K-ras mutated mice. 2. Determine the effect of tobacco smoke exposure on the pancreatitis-induced fibrosis, survival, and carcinogenesis in wild type and K-ras mutated mice 3. Determine the effect of alcoholic chronic pancreatitis and tobacco smoke combination on fibrosis, survival, and carcinogenesis in wild type and K-ras mutated mice. 4. Determine the effect of NADPH oxidase and Akt inhibitions on preventing the effects of alcoholic chronic pancreatitis and tobacco. PUBLIC HEALTH RELEVANCE: Every year, 40,000 Americans are diagnosed with pancreatic cancer; most of them die within one year. Alcoholic pancreatitis and smoking are major risk factors for this devastating disease. The goals of the present project are to understand how alcoholic pancreatitis and smoking induce pancreatic cancer development and to find targets for treatment of the disease. The Major reason why we cannot understand how alcoholic pancreatitis and smoking initiate and promote pancreatic cancer is the absence of pancreatic cancer animal models. That is, animals that present the same characteristics of the human pancreatic cancer and therefore giving the possibility to understand the etiology and the mechanism of development of the disease. This project aims at developing a mouse model of pancreatic cancer induced by alcoholic pancreatitis and tobacco smoke. Further, by understanding the mechanism of pancreatic cancer development we will determine targets for prevention and treatment of the disease. One major outcome of the study is the result of testing the Akt inhibitor, MK-2206, for prevention of the pancreatic cancer induction. This is very important because MK-2206 is now in clinical trials for solid tumors. The results of this project will not only suggest new treatments and/or preventions of pancreatic cancer but also suggest treatment and preventive strategies for other cancers induced by alcohol abuse and smoking.